ES2620968T3 - Polymorphic form of calcium pitavastatin - Google Patents

Abstract

Substantially pure K polymorphic form of pitavastatin calcium, wherein said substantially pure polymorphic form is characterized in that it exhibits an X-ray powder diffraction pattern exhibiting peaks at 3.8, 11.3, 17.4, 18, 1, 24.6 ± 0.2 degrees two theta, said X-ray powder diffraction pattern being obtained using a CuKa radiation of 1.541874 Å, and because it comprises less than 10% of other crystalline forms of pitavastatin calcium and less than 3% of other impurities, and is characterized by having an X-ray powder diffraction pattern as shown in figure 1.

Description

DESCRIPTION

Polymorphic form of calcium pitavastatin.

5 Field of the invention

The present invention relates to a new polymorphic form of calcium pitavastatin, a process for the preparation thereof, pharmaceutical formations containing it, and their uses. The polymorphic form according to the present invention is characterized by high polymorphic purity and chemical and physical stability.

10 high.

Background of the invention

Pitavastatin is the common name for (3R, 5S, 6E) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,515 dihydroxyhept-6-enoic acid. Pitavastatin can be represented by the following structural formula:

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Pitavastatin is commercially available in the form of calcium salt of pitavastatin (1: 2), hereinafter referred to as calcium pitavastatin. It is sold under the brand name Livazo, as a film-coated tablet in concentrations of 1 mg, 2 mg, 4 mg.

Calcium pitavastatin is known by the chemical name bis [(3R, 5S, 6E) -7- (2-cyclopropyl-4- (4-fluorophenyl) -3quinolyl) -3,5-dihydroxy-6-heptenoate] monocalcic, and It can be represented by the following structural formula:

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Pitavastatin is a potent statin that combines effective control of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) with an increase in long-term increases in lipoprotein cholesterol from

High density (HDL-C), and, due to its new structure, is less likely to have drug-to-drug interactions.

It is indicated for the reduction of elevated total cholesterol (CT) and LDL-C, in adult patients with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia, and / or mixed dyslipidemia.

35 Several polymorphic forms of calcium pitavastatin (Forms A, B, C, D, E, F) and an amorphous form have been disclosed.

WO2004 / 072040 describes polymorphic forms A, B, C, D, E, and F, and the amorphous form of pitavastatin

40 calcium. It is disclosed that Form A can generally be prepared from pitavastatin sodium by reacting it with CaCl2 in an aqueous reaction medium. It may contain up to 15% water, preferably about 3 to 12%, more preferably 9 to 11% water. In addition, it is disclosed that Forms B to F can be obtained by treating form A as follows:

45 • Form B can be prepared by suspending form A in ethanol containing water as a co-solvent.

• Form C can be prepared by suspending form A in isopropanol containing water as a co-solvent. Form C can also be prepared from a mixture of isopropanol and a ketone solvent, which contains water as a co-solvent.

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produce small-sized particles in a narrow size distribution, that is, micronized material. As those skilled in the art will appreciate, micronizers use the kinetic energy of collision between suspended particles in a rapidly moving fluid stream (typically air or nitrogen) to cleave the particles. A jet mill is a preferred fluid energy mill. Suspended particles are injected under pressure into a stream of recirculating particles. Smaller particles are carried in flight inside the mill and are swept into a conduit connected to a particle size classifier such as a cyclone.

The material is fed to the micronization system at a controlled feed rate by means of a screw feeder or a vibrating feeder. The jet mill is operated with controlled air or nitrogen pressures. For the Jetmill MC-500 micronizer, the feed rate is 3-40 kg / h, the feed air / nitrogen pressure is 0.5-6 bar, and the crushing air is 1-6 bar.

Micronization can also be achieved with an impact barbed mill. The starting material may have an average particle size of 20-100 micrometers. The material is fed to the mill system at a controlled feed rate by means of a screw feeder or a vibrating feeder. The mill is operated with a controlled speed. For the Alpine UPZ 100, the feed rate is 6-40 kg / h, the mill speed is 7000-15000 rpm.

Calcium pitavastatin in polymorphic form K, as obtained by the method according to the present invention, is surprising and unexpectedly stable in terms of chemical and physical stability. In the context of the present invention it has surprisingly been discovered that the polymorphic form K according to the present invention does not become another polymorphic form when subjected to:

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Stability conditions under stress at 40 ° C / 75% RH (relative humidity) for 1 month in an open or closed container

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humidity condition at room temperature of 90% RH (relative humidity) for 3 days

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mechanical stress-compression force of 8 tons / cm2

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crushing (for example in a mortar).

Table 1 shows the result of a comparison with polymorphic forms known in the art, such as form A, form A with less crystallinity, form E and amorphous form of calcium pitavastatin, which have been tested under the same conditions.

Table 1

Polymorphic shape

40ºC / 75% RH / 1m (open) 40ºC / 75% RH / 1m (closed) Compression force of 8 tons / cm2 25ºC / 90% RH / 3 days

K shape

K shape

K shape

K shape

K shape

amorphous form

amorphous form

amorphous form

amorphous form

amorphous form

form A

form A

form A

form A with reduced crystallinity form A + traces of form E

form E

form E + traces of form A form E + traces of form A form A with reduced crystallinity

form E

form A with reduced crystallinity

form E  form A with reduced crystallinity form A with reduced crystallinity form E

As can be seen from Table 1, the new polymorphic form K proves to be stable when subjected to conditions of stability under stress or compression. This is not true for other polymorphic forms known in the art, which undergo test conditions undergo changes in the crystalline form. On the other hand, the amorphous form, which is stable in terms of physical stability, is extremely unstable in terms of chemical stability, as shown, for example, in WO 2005/063711, while the polymorphic form K according to the present The invention is also stable in terms of chemical stability.

In addition, the polymorphic form K according to the present invention shows surprisingly high thermal stability, that is, stability of a molecule at elevated temperature. Polymorphic form K is more resistant to decomposition at elevated temperatures than polymorphic form A according to WO2005 / 063711, which was shown to be the most stable form of calcium pitavastatin. Polymorphic form K decomposes at temperatures above 248 ° C, while polymorphic form A decomposes at temperatures around 180 ° C. This is evident from the DSC curve, shown in Figure 4. The powder diffraction pattern of the polymorphic form K heated to 220 ° C shows only a small change compared to the diffraction pattern

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of initial state dust (recorded at room temperature). The powder diffraction pattern of a sample that was heated and cooled to room temperature represents the K form with better crystallinity (Figure 8). On the other hand, polymorphic form A shows a decrease in crystallinity during the heating process, and finally at 180 ° C it becomes the amorphous state (Figure 9). At 70 ° C, the powder diffraction pattern of the sample has form A with reduced crystallinity.

In addition to that, the polymorphic form K according to the present invention is a slightly hygroscopic material in contrast to other known polymorphic materials of calcium pitavastatin, which can be referred to as very hygroscopic materials. Hygroscopy is illustrated by dynamic sorption analysis (DVS), as shown in Table 2.

Table 2

Polymorphic shape

Loss on drying at 0% RH, 25 ° C Amount of water sipped at 90% RH

Amorphous form

-0.8% 5.2%

E form

-9.2% 13.7%

Form A with reduced crystallinity

-4.4% 12.4%

K shape

-1.9% 3.3%

Form A

-8.8% 13.9%

The calcium pitavastatin can also be packaged in an inert atmosphere in a container such as a polyethylene bag or a heat-sealed polyethylene laminated bag, preferably in a heat-sealed polyethylene laminated bag in a nitrogen atmosphere. The calcium pitavastatin can be stored at temperatures ranging from 0 ° C to room temperature.

According to another embodiment of the present invention, pharmaceutical compositions or formulations comprising polymorphic form K of calcium pitavastatin as active ingredient are included. Of particular advantage is the fact that the present polymorphic form is surprisingly stable when subjected to standard technological procedures used in the preparation of pharmaceutical formulations, such as granulation, compression or drying.

The crystalline form K of calcium pitavastatin can be formulated in solid dosage forms such as tablets, granules or capsules. Solid dosage forms containing the drug can be manufactured by prior art procedures, such as direct compression, dry granulation, or wet granulation.

In one embodiment of the present invention, a solid dosage form containing calcium pitavastatin is produced by direct compression of a powdered mixture of calcium pitavastatin and at least one additional ingredient selected from stabilizers, diluents, binders, disintegrants, glidants and lubricants, in which the stabilizers used in the weight-to-drug ratio of 1:10 to 10: 1 can be selected from water-insoluble alkaline reactive compounds having a pH of the saturated solution of such alkaline reactant substance in pure water of at least 8.0, preferably 8.5, and still more preferably 9.0, such as oxides, hydroxides, carbonates, phosphates, alkali metal, alkaline earth or aluminum silicates, or mixed inorganic salts, or soluble alkaline reactant compounds in water such as hydroxides, carbonates, alkaline di-and tribasic phosphates (for example, disodium hydrogen phosphate, phosph trisodium ato), and organic bases such as meglumine, arginine, triethanolamine or the like. The diluents can be selected from sucrose, lactose, mannitol, dextrose, sorbitol, trehalose, starch and its derivatives, microcrystalline cellulose. The diluents are preferably used in the range of 10-95% (w / w), more preferably in the range of 50-90%. Binders can be selected from water soluble polymers, such as soluble cellulose ethers such as hydroxypropyl methylcellulose (having a viscosity of a 2% solution in water at 20 ° C below 20 cps (determined according to the USP method), preferably below 15 cps, and still more preferably below 10 cps, hydroxypropylcellulose, which contains not less than 52.0% and not more than 81.0% hydroxypropoxy groups (-OCH2CHOHCH3), hydroxyethylcellulose, methylcellulose, povidone, copovidone, vinyl polyalcohol, and / or water insoluble polymers such as starch and its derivatives and microcrystalline cellulose The binders are preferably used in an amount up to 10% (w / w), more preferably 1 to 8% (w / w ), and still more preferably from 2 to 6% (w / w). Disintegrants can be selected from crospovidone, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium starch glycolate, little hydroxypropyl cellulose substituted containing no less than 5.0% and no more than 16.0% hydroxypropoxy groups (-OCH2CHOHCH3), potassium polyacrylline. Low substituted hydroxypropylcellulose is preferred. The glides can be selected from colloidal silicon dioxide (Aerosil), talc, magnesium trisilicate, magnesium silicate, calcium phosphate, cellulose powder and magnesium oxide. Lubricants can be selected from metal stearates such as magnesium, calcium, zinc or aluminum stearate, sodium starch fumarate, hydrogenated vegetable oils and stearic acid.

In another embodiment of the invention, a solid dosage form of calcium pitavastatin can be

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phenylethanamine), and the aqueous phase was maintained by means of a thermostat at 73 ° C. After the target temperature was reached, 2.2 g of Form K seeds (pitavastatin Ca) were added. Then, in the next 105 minutes a solution of CaCl2 in water (55.0 g of CaCl2x6H2O in 4100 ml of distilled water, preheated to 40 ° C) is gradually added, and the reactor content temperature is maintained at 73 ° C during the addition. The suspension formed is then maintained by means of a thermostat at 73 ° C and mixed for the next 20 hours. The product obtained is isolated by suction filtration using a Büchner funnel and a nitrogen atmosphere, and washed with 600 ml of distilled water (75 ° C).

The isolated product is dried in a vacuum dryer under reduced pressure (<50 mbar) and at a temperature of 40 to 50 ° C, until a water content below 2% is reached.

yield: 171.8 g

water content: 2.0%

HPLC purity of pitavastatin: 99.88% area

HPLC assay as such: 98.8% by weight

Example 5

Phevatatin salt ((3R, 5S, E) -7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhept-6-enoate of (R) -1- Phenylethanamine, 5.0 g), 1M NaOH (10.4 ml) and distilled water (41 ml) in a glass reactor, equipped with a condenser and a mechanical stirrer, in a nitrogen atmosphere and protected from light. The temperature of the mixture is maintained at 22 ° C and stirred until a clear solution is formed. After the formation of a clear solution, the mixture was heated to 40 ° C and MTBE (50.0 ml) was added. The immiscible phases were mixed for 15 minutes at the temperature of the mixture of 40 ° C, and allowed to separate. In addition, the phases were separated, and the aqueous phase was maintained by means of a thermostat at 73 ° C and was used in the following procedure. After the target temperature was reached, 0.05 g of Form K seeds (pitavastatin Ca) were added. Then, a solution of CaCl2 in water (44.0 g of CaCl2x6H2O in 3280 ml of distilled water, preheated to 45 ° C) is gradually added over the next 180 minutes, and the reactor content temperature is maintained at 72-74 ° C during addition. The suspension formed is then maintained by means of a thermostat at 73 ° C and mixed for the next 18 hours. The product obtained is isolated by suction filtration using a Büchner funnel and a nitrogen atmosphere, and washed with 20 ml of distilled water (45 ° C).

The isolated product is dried in a vacuum dryer under reduced pressure (<50 mbar) and at a temperature of 40 to 45 ° C, until a water content below 1% is reached.

yield: 2.9 g

Recovery of (R) -1-phenylethanamine:

The separated MTBE phase was distilled using vacuum distillation at a bath temperature of 40 ° C and a pressure of <50 mbar to a constant mass of the evaporated MTBE residue, m = 0.8 g.

water content: 0.6%

HPLC purity of pitavastatin: 99.75% area

HPLC assay as such: 98.6% by weight

Example 6

Phevatatin salt (3R, 5S, E) -7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhept-6-enoate of ((R) -1- phenylethanamine, 5.0 g), 1M NaOH (10.4 ml) and distilled water (41 ml) in a glass reactor, provided with a condenser and a mechanical stirrer, in a nitrogen atmosphere and protected from light. The temperature of the mixture is maintained at 22 ° C and stirred until a clear solution is formed. After the formation of a clear solution, the mixture was heated to 40 ° C and MTBE (50.0 ml) was added. The immiscible phases were mixed for 15 minutes at the temperature of the mixture of 40 ° C, and allowed to separate. In addition, the phases were separated, and the aqueous phase was maintained by means of a thermostat at 73 ° C and was used in the following procedure. After the target temperature was reached, a solution of CaCl2 in water (44.0 g of CaCl2x6H2O in 3280 ml of distilled water, preheated to 45 ° C) is gradually added over the next 180 minutes, and the reactor content temperature is maintained at 72-74 ° C during the addition. The suspension formed is then maintained by means of a thermostat at 73 ° C and mixed for the next 18 hours. The product obtained is isolated by suction filtration using a Büchner funnel and a nitrogen atmosphere, and it is

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Example F15:

Pitavastatin calcium

4.18 mg

Microcrystalline cellulose

100.00 mg

Lactose monohydrate

170.82 mg

Alumino magnesium metasilicate

26.40 mg

Polyvinylpyrrolidone

16.00 mg

Silica, colloidal anhydrous

1.00 mg

Magnesium stearate

1.60 mg

Coating suspension easy to obtain Opadry 03H28758 white

c.s.

5 Calcium pitavastatin (for example, average particle size of 15.0 µm), microcrystalline cellulose (for example, 102), lactose monohydrate, polyvinylpyrrolidone and magnesium alumino-metasilicate (for example Neusilin FL2) were homogeneously mixed. Magnesium stearate and colloidal anhydrous silica were added to obtain the compression mixture. After compression, the tablets obtained (320 mg / tablet, diameter: 10.0 mm) were coated with film with an easy-to-obtain film coating suspension. The theoretical weight of

10 film-coated tablets was 330 mg.

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Claims (1)

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